I note in the second to last question that Hudson refers to using veterinary applications to hasten the arrival of human treatments. I proposed this last May in response to a post about the Dog Aging Project involving rapamycin. https://www.fightaging.org/archives/2015/05/the-dog-aging-project.php
I saw that this treatment would only slow aging and not rejuvenate dogs so I had the idea of using senolytics. Animal lovers would eagerly pay for a chance for more time with their pets and would generate a flood of publicity for SENS research. I emailed SENS about the idea of a Robust Dog Rejuvenation (RDR) being perhaps a better alternative to RMR due to this reason. Michael answered that mice were still superior due to their short lives, low cost, and prior gene therapy experience. He also commented that that extent of senolytic cell burden in dogs is unknown and hence also unknown is the amount of the potential benefit.
Apparently, Hudson disagrees and believes that some sort of senolytic “companion animal” treatment is feasible and will accelerate human treatments. It will probably require FDA approval, however:
http://www.fda.gov/AnimalVeterinary/default.htm
If they are successful, expect a stampede of animal lovers to pony up which will fund more human research.
Those are some big claims about their liposomal vector technology. If true it would revolutionize gene therapy. Which is why I am a bit skeptical about their claims.
In fact… someone might want to suggest to Gary Hudson that he contact Crestview Genetics or Kheiron Laboratories to see if they are interested in investing to extend the useful lives of Polo Ponies. The technology may be a bit early stage, but I’m sure they would be interested at some point.
Very promising post! In regards to the mice versus dogs as the next subject which will ultimately lead to the most funding, there is no comparison. The connection between people and canine is primordial, with co-evolution going back longer than recorded history. Many people would rather see Homo sapiens go extinct before dogs. An many owners would gladly die before their dogs do. Pursuing this strategy is he right way to go.
If our non profit lab launched a small fundraiser to test with Oisin how do people feel about donating to research that benefits a for profit? Do you feel that getting the therapy to clinical is the important thing here or should we not test it?
We could do an n=40 lifespan test for ~12k Euro and it would really help Oisin proceed faster. Would the community support us?
As for me, if the money is only for the lifespan test in the MMTP labs, I have no problem with that. If the money is given directly to the company to do the test, I’m unsure about what to do (I would probably not give it).
Can’t comment about the underlying science, but I like Gary’s last sentence: “money is only important to me in that it’d allow us to move quickly onto the next aging-related problem”. That’s the spirit! And that’s how Gary will benefit from his investment in the long run: the better you further research, the better your own outcomes.
@Steve: there surely are ways to cooperate between non- and for-profits.
What if *they* fund you, basically outsourcing some tests to you?
@Steve H – I’d have to worry if funding is that tight for Oisin that they can’t fund a 12k test out of pocket. The Glenn Foundation gave the Mayo Group 3 million USD to carry out their testing in normally aging mice back in 2011. I don’t think costs can have come down that much since then.
For clarification the MMTP would testing using their supplied system but we would be testing independently and free to publish results as we wished without restriction.
Steve, your requirements do not sound unreasonable for Oisin to fund you in full.
Unless this is to be offered offshore and beyond the FDA’s long reach, then this is many years away from availability. Offering the treatment to pets is a fine idea but offering it in less regulated countries is the smartest way to both profitability and helping actual people in that place we like to call the real world.
Oisin is conducting our own lifespan study but is (subject to acceptable terms of use) willing to supply the vector + construct to MMTP to allow them to conduct an independent parallel replication (rather than having to wait for ours to be done in two years or so). But replications should not be funded by the company that might stand to benefit; that could cause some observers to call into question the results.
You have a point, Gary. Then it’ll be up to the community to raise the necessary funds.
Glad that you’re willing to cooperate, in any case 🙂
Gary is right and mmtp is working on a way to make happen. Watch this space we are hoping to take oisin up on their fantastic offer
That would be a very good system, Gary. Totally agree!
“The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses.”
The UK Cystic Fibrosis Gene Therapy Consortium has been struggling for years with trying to deliver gene therapy to the lungs. They tried plasmids in inhaled liposomes, but only seemed to somewhat stabilize the disease and didn’t get very good transfection rates. They are pursuing a modified Sendai virus approach now.
If this Liposome technology works, why not try it out for correcting the single gene defect that causes CF? You’d be awash with money if that panned out. Look at Vertex Pharmaceuticals and Kalydeco.
It works sufficiently well enough for our purposes, which are not necessarily the same as those who need to conduct permanent gene therapy. We recognize the potential value of our technological approach. We are considering all our options, is all I can says this time. And we want to present irrefutable proof of process before we start looking at other forms of treatment.
Thanks for the reply, and good luck!
Let me follow up on my earlier conversation with Morpheus (as he relays it above). I’m much more enthusiastic about Oisin going the veterinary route as an orthogonal route to maraket with their approach than I was (and am) about testing senolytics per se as part of Robust Dog Rejuvenation.
First, and most importantly, the state of the science is much stronger now than it was then: at the time, we had some exciting but still limited outcomes for one senolytic protocol, whereas now we have multiple studies with multiple outcomes (including lifespan) using multiple routes of senescence and multiple senescent cell-clearing treatments (INK-ATTAC, 3MMR-p16, dasatinib/quercetin, Navitoclax) performed in more-or-less normal mice. And Oisin has already done some preliminary mouse work with their approach, and is planning to to a lifespan test. That’s a very strong science base in mice, and makes the case for work in other organisms.
Second, the Oisin tech is much closer to a true rejuvenation biotechnology for the ablation of senescent cells: it directly targets cells based on an indicator of their senescence status (rather than nonspecifically inhibiting generic cell survival pathways and relying on the differential reliance of senescent cells on same with predictable risks of the “gerontological” approach of messing with metabolism to develop anti-aging therapies), and has a cleaner (in principle) mechanism for execution (which again avoids interference with metabolic pathways on which our other cells rely).
So it’s much more realistic to think that it could be translated into a true rejuvenation therapy for humans or even dogs than dasatinib/quercetin, and doing so is a prospect about which I’m much more enthusiastic in any case.
In principle, then, this could become a true human rejuvenation biotechnology, particularly if it can be either made more specific to senescent cells or several different variants can be developed to target different subtypes thereof. The veterinary route is (a) scientifically valuable in itself, (b) will rouse intense public excitement and drive acceptability and acceptance of the reality of intervention in degenerative aging, and (c) is a potential strategy to bring it more rapidly to market for human use.
On RDR, my sundry concerns still apply entirely: RMR per se is still a critical benchmark, and if we had the full panel of rejuvenation biotechnologies required to achieve it, (a) it would be far preferable to use a tech in principle similar to Oisin’s than a senolytic drug, and (b) the mouse remains the better organism in which to do the test. It takes two years to take an early-old mouse and double its remaining life expectancy; the equivalent in a dog is something like eight.
Make no mistake, though: I agree entirely on the overarching point. the day that people first see their dogs (and their friends’ dogs) living substantially longer and healthier lives (and perhaps manifestly rejuvenated) after receiving rejuvenation treatments will be a true watershed in the public’s enthusiasm for and acceptance of treating biological aging like the medically-tractable, fatal degenerative disorder that it is. And that is a prospect that excites me very much, and should excite us all.
I’d urge caution about the prospect of going the veterinary route for SENS stuff. For some time, several companies have provided stem cell treatments for osteoarthritis in horses (treatments which seem to be supported by decent studies) and dogs (great anecdotes but not so robust studies), but we still don’t have a single FDA-approved, stem cell treatment for osteoarthritis or any age-related disease in humans despite adequate amounts of funding and a big head start. At the very least, senolytics-focused companies should determine if they can avoid the quagmire that the veterinary stem cell companies have fallen into.
I’m also a bit pessimistic about the amount of SENS support that the public is going to provide for the following reasons:
1) The public usually doesn’t care what approaches are used to treat disease and leaves it up to mainstream experts to decide what biomedical research gets funded. Stem cell research is the only exception I can think of but that’s probably a result of pushback against research restrictions enacted by religious fanatics.
2) While there’s plenty of public support for stem cell research, there’s no comparable support for aging research even though stem cell research is part of aging research.
3) Increased support for aging research doesn’t necessarily translate into lots of support for SENS. Calico and HLI are prime examples of this. And the public is a heck of a lot more ignorant about aging research than the founders of those organizations.
4) There are plenty of mouse rejuvenation claims floating around, yet there’s no big public push for more aging research. And in any case, once RMR actually arrives, the public might have become too cynical (if it hasn’t become so already) to take it seriously no matter what anyone tells them.
5) Most of the funding gap exists before RMR (or RDR), not after.
6) I don’t see why the public would get intensely excited if Fido lives a few years longer than average; this amount of lifespan extension just seems too small to matter.
Michael, I appreciate the explanation of your standpoint, thank you.
In terms of PR, though, I’m afraid that the veterinary route would lead the average people to think of it as a “vanity treatment”, much like people cloning their dogs, and comforting them in their stereotype that “life extension is a selfish wish made by selfish persons”.
So I would expect a scientific acceptance, but a social one, not so much. There will be backlashes.
Thank you Gary Hudson for saying this:
” When people asked me what I wanted to do with my life, I routinely and only half jokingly replied – “fly to the stars and live forever”
That is what i have been saying for the past 30 years. I registered Trade Mark:
IMMORTALITY SYSTEM IS Extra Terrestrial Migration — Gene Engineering
in 1995 und put up the Forum http://www.immortalitysystems.com in 1997
Remember, the only limit is our imagination. AD ASTRA alfred
Have they published or is there a patent of the liposomal technology they are using. I would be very interested to see what liposomes the are using.
Today (10.29.16) the Washington Post published a short piece on Jeff Bezos (WaPo owner!) investing in Unity Biotech. This set me to Googling, Binging, etc., and led me here. As a scientifically literate layman entering the halls of octogenarians, I am profoundly interested in the topic. “Informed consent” should allow one to volunteer for human trials, and I am informed enough to consent credibly. Why can’t the army of olde farts join the battle for rejuvenation?
Indeed, the more aged volunteers for trials, the more investors and the more donators… the faster we will get appropriate therapies. People from all age groups will benefit.
I hope you will keep reading Fightaging along with the rest of us, enroll in trials if your profile interests companies/researchers, and maybe spare some money for the various fundraisers pertaining to SENS.
Senescent cells clearance could be one of the most interesting fields of research in Neurodegenerative disorders like Alzheimer’s (AD) and Parkinson’s (PD).
Like always, the results are preliminary but a couple of them should be highlighted:
– Amyloid β Protein can increase the levels of p16 in AD transgenic mice and this correlates with a cognitive impairment (PMID: 27453234). Nevertheless, the authors did work performed experiments where they cleared these p16 positive neurons so a possible recovery still needs to be assessed.
– Non-neuronal cells (astrocytes) exhibit high levels of Senescent markers in PD brains when compared to disease-free samples (reviewed in PMID: 25281806). Some believe that these senescent cells could be the underlying mechanism for neuroinflammation.
Do you think that Senescent cell clearance would be an effective treatment for neurodegeneration?
Particularly considering that in most of these diseases, an accurate medical diagnosis is obtained when the majority of neurons in the affected areas are already compromised (in PD, 80% of neurons in the Substantia Nigra pars compacta have disappeared when patients exhibit the first motor symptoms).
Or do you believe that this technique is dependent on better early-stage diagnosis to really be effective?
I certainly think that senescent cell clearance would be a beneficial component of an overall strategy for neurodegeneration. The evidence for a role of senescent cells in AD is still rather preliminary, but is suggestive, and there is rather strong evidence for a role of SC in Parkinson’s. In fact, Julie Andersen of the Buck Institute presented work at the Rejuvenation Biotechnology 2014 showing that clearing senescent cells in the brains of animals substantially protects their dopaminergic neurons and motor function against paraquat, a neurotoxin that causes a PD-like syndrome in mice and humans alike by selectively killing dopamine-producing neurons in the brain.
I don’t believe that this technique is dependent on early-stage diagnosis to really be effective, but I would certainly expect that earlier clearance would be better, preëmpting a proportionate number of dopaminergic neurons’ death and thus necessitating less cell therapy to replace them.
Today’s topic is another young senescent cell clearance company that I’ve been enthused about since early last year: the company is Oisin Biotechnologies, founded and initially self-funded by Gary Hudson and Matthew Scholz. The Oisin researchers have what is arguably the best of current approaches to senescent cell removal and are to my eyes closer to implementation in humans than is UNITY. The early Oisin prototype work was known to the SENS Research Foundation folk soon after they started – this is a small community – but the path to getting the company seed funding in 2014 from first the Methuselah Foundation and then a few months later by the SENS Research Foundation was driven by David Gobel of the Methuselah Foundation. That funding paid for a successful proof of concept demonstration in mice, and earlier this year a new round of fundraising took place to set in motion the next stage of clinical development. I’m pleased to say that Fight Aging! participated in that round, a small helping hand for this important development project. More on that tomorrow, but for now let me turn you over to Gary Hudson of Oisin Biotechnologies to explain how they are approaching the challenge of senescent cell clearance to produce a rejuvenation therapy:
Who is Oisin Biotechnologies, how did you meet and decide that this was going to be your next venture?
Oisin was founded by two individuals, Matthew Scholz, who came up with the basic scientific approach for our first technology, and myself, who provided the initial angel funds along with the Methuselah Foundation and later, the SENS Research Foundation. I’m serving as Acting CEO while the company is in virtual mode.
After the talks, Matthew and I were musing about potential ways to kill senescent cells that could be viable in humans. (By this time Matthew had spent a great deal of time researching vectors for gene therapy and was working with a non-viral suicide gene developed at Baylor and already used in humans). Matthew said he thought we could use a particular liposomal vector he’d come across in the past with the suicide gene to kill senescent cells in humans. He said he was too busy with and committed to Immusoft to take on another project, and it was so different from Immusoft’s technology that it would likely be a detrimental distraction to their work if he tried to pursue it there. But the more we talked about it, the more compelling it sounded. Finally, I just said, “This has to happen. If you write this up, I’ll fund it myself. I’ll be the CEO and raise the rest of the money we need to see if it works.” So, we licensed the liposomal vector, filed the first patent and built our prototype.
You are clearing senescent cells; what is the approach you are using, and how far along is it?
Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one in the Baker paper that kills p16–expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses.
There’s a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn’t have any preference for senescent cells. It delivers the gene sequence to healthy and senescent cells. We don’t target based on surface markers or other external phenotypic features. As Matthew likes to say “we kill cells based on what they are thinking, not based on surface markers.” So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence – the suicide gene – will be transcribed and drive the cell to apoptosis. However, if p16 isn’t active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don’t use a virus to deliver our gene sequence, and our liposomal vector isn’t immunogenic, our hope is that we should be able to use it multiple times in the same patient.
So far we have demonstrated that our vector and gene sequence can efficiently and selectively kill senescent human cells in culture, and that we can target senescent cells in vivo in mice treated with chemotherapy. The next step is to show that our approach can achieve senescent cell clearance along the lines of the work done at the Mayo Clinic, but in a translatable model – without the use of their transgenic INK-ATTAC mice. After all, we aren’t transgenic mice. As exciting as their work is, the data in those papers is purely an academic exercise; the treatment they gave the mice would be of limited value in humans. Our hope is that we will have our first data from our next studies this year.
How does your approach differ from that of UNITY Biotechnology?
I don’t have any first-hand knowledge of the activities underway at UNITY; you and I have probably read the same coverage of their efforts. It appears that they are focused primarily developing small molecule drugs to kill senescent cells. As I was describing earlier, we are taking a transient gene therapy approach. Put another – less conventional – way, we’re effectively killing senescent cells with a genetic computer program that we upload with our liposomal vector.
The beauty of our approach compared against a small molecule is that, if we want or need to, we can very rapidly tailor our treatment to kill a specific kind of cell under a specific circumstance, or tailor it to avoid a specific kind of cell – all by just changing the gene sequence we deliver. What we really have is a platform that allows us to selectively kill cells based on very specific and customizable genetic criteria. That kind of flexibility just isn’t possible with a small molecule drug.
You just raised a funding round, what is the plan for the next year or so?
As I mentioned, all of the elements of our approach are working well, so now it is time to combine the pieces and do the work required to turn a promising candidate into a life-changing therapeutic. We hope to conduct several in vivo studies in the near future to assess the impact of the treatment on senescence induced by various means. If time and money permit, we’ll also begin to try to understand what dose ranges are optimal, how many treatments might be required to dramatically diminish senescent cell body burden, and so on. We’d also like to set up for a large lifespan study in mice and maybe other animals as well. We’ll be looking to make alliances with pharma partners that are focused on particular FDA indications, such as COPD, BPH, and so on.
What is your take on the bigger picture of SENS and the goal of ending aging?
I’ve been interested in this topic since I was a teenager, right at the time we were doing real moonshots (not the Google equivalent). When people asked me what I wanted to do with my life, I routinely and only half jokingly replied – “fly to the stars and live forever” – borrowing a theme from the science-fiction writer James Blish. But I found that it was hopeless to expect progress on the aging front in 1969, so I turned my attention to space, and became one of the first commercial space entrepreneurs. After 45 years in that “space” I’m now ready to spend some time focusing on engineering a solution to the problems of aging.
I was also the first major contributor to the SENS project. I helped fund the first SENS conferences and also the Methuselah Mouse Prize. I believe in the basic SENS notion of treating aging as an engineering problem – repair, replace, and restore function and you will both increase healthspan and move towards escape velocity.
What do you see as the best approach to getting nascent SENS technologies like this one out into the clinic?
This is a complex question. Personally, I’m not too interested in the normal “pharma” path to the clinic. That’s not to say that we (or more likely some future pharma partners) won’t pursue this route, but the costs have to be weighed against the need to move therapies into public view, soon. So it’s necessary to examine alternative routes to the clinic. One area that is slightly orthogonal to the traditional path is to work on veterinary and companion animal treatments before a human product. Working out our strategy is a significant part of my near-term job, with the other focus being the next major raise of dollars in our Series A, sometime in 2016.
If this works stupendously well and everyone involved becomes wealthy, what next?
Essentially all of my ownership stake in Oisin will go into my nonprofit (to be announced shortly) and will be used to advance cutting edge translational medicine. But while I hope we make a profit for our investors’ sake, my ambition in helping found Oisin has been to move the needle on true anti-senescence therapies. If we’re successful, yes, we have a good chance to make money. But money is only important to me in that it’d allow us to move quickly onto the next aging-related problem, and that’s what we’ll do.
To the degree that Oisin succeeds, that success will channel funds into the Methuselah Foundation and SENS Research Foundation, as well as to a number of individuals who are already strong supporters of the longevity science cause. These are people who, like myself, are well aware that the only rational use for excess money is to fund the development of radical life extension technologies. What use is wealth to the sick and the dead? The true power of wealth in our day and age is that it can now be spent to build the technologies needed to defeat aging and illness. If only it was the case that more people realized this, we might be so much further ahead.
This content was originally published here.
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